The invention concerns membranes of diisocyanate addition polymers such as polyurethanes, and polyureas, for hemodialysis and/or hemofiltration, as well as a process for the manufacture thereof.
Hemodyalysis is a method by which determined substances such as urea, uric acid, creatinin, among others, are separated from the blood in the course of a so-called dialysis. Such a treatment is necessary for patients who have kidney insufficiency. During dialysis, the blood is led from a blood vessel through an artificial kidney in which it flows along a semi-permeable membrane. An appropriately-composed rinsing liquid is located on the other side of the membrane into which the toxic substances travel through the semi-permeable membrane. The cleaned blood is then led back to the body.
When patients who possess a kidney-insufficiency are not subjected to a dialysis treatment, also called a blood-washing, within determined intervals of time, the blood becomes so strongly enriched with these harmful substances that sooner or later, death occurs.
Previously, most membranes employed for a hemodialysis were of a cellulosic basis, namely membranes of regenerated cellulose, particularly Cuprophan.RTM. membranes, which have been prepared according to the so-called cuproamine technique. Moreover, an entire series of hemodialysis membranes are still on the market constructed e.g. on the basis of cellulose acetate.
Cellulose membranes today belong to the standard membranes which work with a high degree of reliability and for the production of which so much experience has been meanwhile collected that this production is controlled with satisfactory certainty. The characteristics of these Cuprophan membranes can be readjusted reproducibly, and it is possible to obtain constant flow data, permeability values and selectivities. Cuprophan membranes have proven themselves in medical use. It has also been possible to collect much experience during the manufacture of modules and complete dialysis devices in which Cuprophan membranes are employed so that manufacture of such arrangements no longer causes principle difficulties. Accordingly, membranes based upon cellulose have been employed worldwide with great success for now up to 15 years, and very many patients have been aided in this manner, providing very extensive numerical material about hemodialysis with cellulose membranes, and in numberless publications hemodialysis with the employment of cellulose membranes is subjected to a critical analysis. Based upon this extensive material, and particularly also with evaluation of statistical tests, man is better equipped today to survey the situation as to what needs are still present concerning the employment of cellulose membranes and in what direction examinations should be made for possibilities for further improvements.
It has thus been shown that during dialysis treatment with cellulosic membranes, within the first hour of treatment so-called leukopenie occurs, i.e., a clear drop in the number of leukocytes is to be observed, which generally is only of a temporary nature and indeed, after a short time, returns by itself to the normal level.
In some scientific publications this leukopenie has been discussed in connection with so-called dialysis discomfort phenomena which, among others, is made conspicuous by a certain indisposed state of health of the patient.
It is, moreover, known that cellulose surfaces in contact with blood will activate the immune system of the body, i.e., a defense reaction is set in motion against the foreign surface. It would therefore, be advantageous to have available a membrane for dialysis which does not display this disadvantage, is thus biocompatible, in particular compatible with blood, which, however, simultaneously displays favorable dialytic characteristics. It has already been attempted to manufacture hemodialysis membranes from numerous synthetic polymers, which however, cannot be performed in practice be it that they do not possess the desired dialytic characteristics, such as permeability and selectivity, or be it that they are inferior to cellulose membranes with regard to their compatibility with blood.
Whereas, with hemodialysis the driving force for the separation process is a concentration difference, and the separation of the material occurs based upon a diffusion, the driving force with hemofiltration is a pressure difference. Since with hemofiltraton amounts of liquid are withdrawn from the blood which are again required by human blood circulation, it is necessary to provide corresponding amounts of electrolyte solution for reinfusion.
Dialysis depends mainly upon the diffusive characteristics of the membrane, in which connection, in addition to the specific characteristics of the membrane, such as polymeric construction, structure and the like, also the thickness of the membrane plays a role. During filtration, in contrast, it is mainly the hydraulic permeability of the membrane which is of significance, so that appropriate flow rates are assured. Those membranes which approach the required hemodialysis characteristics, generally have a smaller thickness which frequently lies at 30 .mu.m and below.
For the combination of hemodialysis and hemofiltration, likewise membranes are employed with small thickness but significantly greater permeability than is the case for pure dialysis.
Upon hemofiltration, the membrane thickness is of less significance, particularly when through asymmetrical construction of the membrane high hydraulic permeabilities are obtained even with thicknesses of 100 .mu.m. Such membranes are, however, on account of the great diffusion pathway, less suitable for dialysis.
It is known that polyurethanes are polymers which are biocompatible. Thus, M. Szycher and coworkers in "Elastomerics" March 1983, p.11, describe what role polyurethane can play in artificial hearts. Apart from several more generally held structural formulas and likewise generally held indications for the manufacture of polyurethanes from the most different starting materials, no concrete statements are given as to how the there-described polyurethane should be manufactured. However, the paper provides nothing about the manufacture of membranes which are suitable for hemodialysis and hemofiltration.
Indeed, a series of publications is known in which the employment of polyurethanes and polyureas is mentioned for the manufacture of hemodialysis membranes.
Thus, in FR-PS No. 1 307 979 are described an arrangement and a process for the treatment of solutions using semipermeable membranes. With the there-described separation operations, one can include the techniques such as osmosis, reverse osmosis, dialysis, ultrafiltration, among others. In addition, to polymers based upon cellulose, also numerous synthetic polymers, among others polyurethane, are generally mentioned. However, indications as to how these polyurethanes are supposed to be constructed and, in particular, as to how a hemodialysis membrane is supposed to be manufactured from polyurethanes are not to be withdrawn from this patent.
Lyman et al describe a series of membranes of polyurethane which are supposed to be suitable for hemodialysis in Trans. Amer. Soc. Artif. Int. Organs, 1965, vol.XI, pp. 91-94 and in Annals, New York Academy of Science, 146(1), pp. 113-118 (1968). The there-described polyurethanes are constructed on the basis of polyglycols, lower-molecular diols and diphenylmethane diisocyanate. It has, however, turned out that the statements made by Lyman are not sufficient in order to be able to manufacture membranes useful for daily employment. Thus, one cannot manufacture, reproducibly, membranes with uniform characteristics using the statements made in these references, in particular the stability of the there-described membranes leaves much to be desired. Upon a hydrolytic degradation of the polyurethane, aromatic amines can be produced, which are known for their toxicity and which it is presumed are included with the carcinogenic substances.
In the Japanese publication No. 81/37007 similarly constructed polyurethanes are described for the manufacture of dialysis membranes, which possess, however, the same disadvantages set forth above.
In DE-OS No. 2 355 073, a process is described for the manufacture of polyurethane solutions, whereby the polyurethane can be prepared from numerous starting materials. Microporous foils, which are prepared according to the teachings of DE-OS No. 2 355 073, are indeed suitable for microfiltration, but are, however, completely unsuitable for employment in hemodialysis and hemofiltration since they also pass through higher molecular substances characteristic of the body, such as proteins, which is undesirable.
When one works the Example 1 of DE-OS No. 2 355 073, using cyclohexane diisocyanate as aliphatic diisocyanate, one obtains only lower-molecular substances, insoluble in dimethylformamide. Also upon addition of hydrazine, is produced no solution because polyurethane precipitates. Whether or not already in the literature and in an entire series of patents, many indications are to be found to manufacture membranes from polyurethanes or polyureas, i.e., from polyaddition polymers, which also are supposed to be suitable for hemodialysis, there still exists a need for improved membranes for hemodialysis and/or hemofiltration, based upon biocompatible diisocyanate addition polymers, as well as for processes for their production.